Our long-term goal is to develop a targeted, polymeric carrier that can be utilized to deliver pro-apoptotic peptides intracellularly to cancerous cells in vivo. We are proposing to use "smart" polymer carriers that are capable of protecting their therapeutic cargo and traveling through the body in a stealth-like fashion at physiologic pH. Upon cellular uptake and entry into more acidic, endosomal compartments, smart polymers become hydrophobic, which makes them membrane disruptive and allows their release into the cytoplasm. We plan to use the RAFT polymerization method, which allows for controlled polymer synthesis and subsequent conjugation to both therapeutic peptides and targeting molecules. In this way, a pharmaceutical will be developed that localizes preferentially to cancerous cells and delivers a peptide that will trigger cell death. Based on this concept, the overall objective of this work is to develop a tumor cell specific polymer- based peptide drug that triggers apoptosis in cancerous cells while avoiding toxicity in healthy tissues. We will build toward this goal through three main aims. Aim 1 will be to develop a "smart" polymer-peptide conjugation scheme that will induce death in cultured cancer cells. Aim 2 will involve developing a strategy to specifically target our drug to cancer cells, and we will validate the targeting efficiency using a mouse tumor model. Aim 3 will be to build on our findings from Aims 1 and 2 to design an optimized tumor- targeted, pro-apoptotic peptide polymeric delivery system and then test its ability to reduce tumor growth in a mouse model. Collectively, the outcomes from these aims have the potential to establish a new paradigm for the design of pharmacologic agents to deliver bioactive peptides that effectively modulate apoptosis or other biological processes for the treatment of cancer and other pathologies. Relevance to Public Health- Conventional cancer treatments, such as radiation and chemotherapy, do not directly target cancerous cells. As a result, they are not always effective and also produce substantial toxicity within the patient's healthy tissues. We are proposing a strategy that will specifically target cancer cells and attack them at the very underpinnings of their tumorigenic transformation, thus increasing the antitumor capacity while minimizing negative side effects